Researchers Led by Penn Vet Uncover the Delicate Protein Balance Behind the Immune System Response

PHILADELPHIA -– A team of researchers from the University of Pennsylvania School of Veterinary Medicine has identified the protein interactions involved in the immune system process that fights infection yet, in certain inflammatory diseases, runs amok and attacks friendly tissue.

The Penn team, led by Christopher Hunter, chair of the Department of Pathobiology at Penn Vet, has identified the pathways that lead to the production of the signaling protein, or cytokine, Interleukin 10 (IL-10) which plays an important role in regulating the balance between the protective white blood, or T, cell response and one that is pathological and out of control.

While IL-10 has long been recognized as a major anti-inflammatory factor, the events that lead to its production have been poorly understood. According to the researchers’ findings, messenger proteins Interleukin 27, or a combination of Interleukin 6 and another type of messenger molecule called transforming growth factor beta, induce production of IL-10. These results suggest that modulating these messenger molecules could increase IL-10 concentrations that temper overactive immune responses.

This information sheds new light on the immune-system response and may provide directed means to intervene in severe autoimmune diseases such as colitis, multiple sclerosis and arthritis.

“The deeper we delve into the role of cytokines in the immune system response, the more we realize that they are part of an elaborately balanced system kept in check by the conflicting regulatory functions of the cytokines themselves,” Hunter said. “When combined with the work from our colleagues at Schering Plough, Harvard and Jefferson University, these studies provide new insights into the pathways that can be used to temper autoimmune inflammation.”

Although there are many sources of IL-10 in the body, the details of how it is synthesized were poorly understood. Hunter’s team determined that the process begins with cytokines IL-27 and IL-6 inducing production Th1 , Th2 and Th17 T cells and concludes that cytokines like IL-27 can promote the ability of these cells to produce IL-10. The effect was dependent on the transcription factors STAT1 and STAT3 for IL-27 and on STAT3 for IL-6.

Researchers tested this hypothesis by removing the IL-27 receptor from genetically engineered mice. Once infected with disease, the mice were unable to generate T cells producing IL-10.

In prior studies, Penn researchers learned that Interluekin-27 was involved in the immune-system response by limiting the duration and intensity of white blood activation, an "off switch" to the cascade of messenger proteins that serve to further activate the immune system. Prior to their research, the general assumption among scientists was that IL-27 promoted inflammation.

The research was performed by Jason Stumhofer, Jonathan Silver, Tajie Harris and Hunter of the Department of Pathobiology at Penn Vet; Arian Laurence and John O'Shea of the Molecular Immunology and Inflammation Branch of the National Institute of Arthritis and Muskoskeletal and Skin Diseases; Paige Porrett and Laurence Turka of Penn’s School of Medicine; Matthias Ernst of the Ludwig Institute for Cancer Research in Victoria, Australia; and Christiaan Saris of the Department of Inflammation Research in Thousand Oaks, Calif.

The study was supported by the National Institutes of Health, Scholler Foundation, Marie Lowe Cancer Center, Commonwealth of Pennsylvania and National Health and Medical Research Council of Australia.